DOCK1

Chr 10

dedicator of cytokinesis 1

Also known as: DOCK180, ced5

NCBI Gene: 1793 ENSG00000150760 UniProt: Q14185 OMIM: 601403

This protein functions as a guanine nucleotide exchange factor that activates Rac GTPases, regulating cytoskeletal rearrangements essential for phagocytosis and cell migration. Mutations cause autosomal recessive combined immunodeficiency characterized by severe infections due to defective phagocytosis and impaired immune cell function. The gene is highly constrained against loss-of-function variants (LOEUF 0.341), reflecting its critical role in immune system development and function.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the dedicator of cytokinesis protein family. Dedicator of cytokinesis proteins act as guanine nucleotide exchange factors for small Rho family G proteins. The encoded protein regulates the small GTPase Rac, thereby influencing several biological processes, including phagocytosis and cell migration. Overexpression of this gene has also been associated with certain cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.34

Clinical Summary— DOCK1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 309 VUS of 397 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.34LOEUF

pLI 0.007

Z-score 7.49

OE 0.25 (0.18–0.34)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.41Z-score

OE missense 0.79 (0.74–0.83)

808 obs / 1025.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.25 (0.18–0.34)

0≤0.351.4

Missense OE?0.79 (0.74–0.83)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 29 / 116.1Missense obs/exp: 808 / 1025.4Syn Z: 0.02

This gene — mechanism propensity

0.6841th %ile

GOF

0.6735th %ile

LOF

0.3357th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

397 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS309

Likely Benign18

Conflicting1

Likely Pathogenic

309

VUS

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	1	0	0	0	1
VUS	1	308	0	0	309
Likely Benign	0	13	0	5	18
Benign	0	0	0	0	0
Conflicting	—				1
Total	2	321	0	5	329

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

79 pathogenic / likely-pathogenic (of 110) ClinVar copy-number / structural variants overlap DOCK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →